Zusammenfassung
Das aktuelle Therapiekonzept zur Behandlung des fortgeschrittenen Ovarialkarzinoms der FIGO-Stadien III und IV besteht aus einer chirurgischen Tumorresektion mit sich anschließender Chemotherapie. Die First-Line-Chemotherapie des Ovarialkarzinoms setzt sich aus einer Kombination eines Taxans, z. B. Paclitaxel, mit einer Platinverbindung, z. B. Carboplatin, zusammen. Die Mehrzahl der Patientinnen entwickelt allerdings, aufgrund der Entwicklung von Chemotherapieresistenz, ein Rezidiv. Es ist daher von fundamentaler Bedeutung, die zellulären Mechanismen, die Resistenzen gegenüber Taxanen und Platinverbindungen verursachen, aufzuklären. In den vergangenen Dekaden konnten über die Entwicklung und experimentelle Untersuchung von verschiedenen In-vitro-Modellsystemen diverse Faktoren gefunden werden, die an Resistenzen beteiligt sind, wie z. B. Mitglieder aus der Familie der Adenosin Triphosphate Bindungs Cassette (ABC)-Transporter, Faktoren, die an der Regulation des Zellzyklus und apoptotischer Signalwege beteiligt sind und viele andere. Eine mögliche klinische Relevanz dieser Faktoren zur Prädiktion wurde in vielfältigen klinisch-pathologischen Studien untersucht. Bisher wird die klinische Bedeutung in der wissenschaftlichen Literatur sehr kontrovers diskutiert. Es sind daher dringend weitere „translationale“ Studien erforderlich, die Erkenntnisse aus der Grundlagenforschung für die klinische Praxis nutzbar machen können.
Abstract
Surgery followed by chemotherapy is the standard therapeutic treatment for advanced, FIGO stage III and IV ovarian carcinoma. First-line chemotherapy for ovarian cancer consists of a combination of a taxane, e.g., paclitaxel, and a platinum-containing drug, e.g., carboplatin. However, the majority of patients suffering from ovarian cancer will relapse due to the development of drug resistance. Thus, it is of major importance to identify the cellular mechanisms that mediate resistance against taxanes and platinum drugs. In the past decades various factors involved in these types of drug resistance have been identified by the experimental investigation of in vitro model systems, e.g., different members of the adenosine triphosphate binding cassette (ABC)-transporter family, factors involved in the regulation of cell cycle and apoptosis, and many others. These factors have also been analysed with respect to their potential clinical impact as predictive factors in clinical settings. So far, the clinical relevance of these factors is still controversially discussed in the scientific literature. Further “translational” studies are therefore necessary which may help to transfer knowledge from basic science into clinical practice.
Schlüsselwörter
Ovarialkarzinom - Chemoresistenz - Taxane - Cisplatin
Key words
ovarian cancer - drug resistance - taxanes - cisplatin
Literatur
-
1
Agarwal R, Kaye S B.
Ovarian cancer: strategies for overcoming resistance to chemotherapy.
Nat Rev Cancer.
2003;
3
502-516
-
2
Arts H J, Katsaros D, de Vries E G, Massobrio M, Genta F, Danese S, Arisio R, Scheper R J, Kool M, Scheffer G L, Willemse P H, van der Zee A G, Suurmeijer A J.
Drug resistance-associated markers P-glycoprotein, multidrug resistance-associated protein 1, multidrug resistance-associated protein 2, and lung resistance protein as prognostic factors in ovarian carcinoma.
Clin Cancer Res.
1999;
5
2798-2805
-
3
Beeghly A, Katsaros D, Chen H, Fracchioli S, Zhang Y, Massobrio M, Risch H, Jones B, Yu H.
Glutathione S-transferase polymorphisms and ovarian cancer treatment and survival.
Gynecol Oncol.
2006;
100
330-337
-
4
Bourhis J, Goldstein L J, Riou G, Pastan I, Gottesman M M, Benard J.
Expression of a human multidrug resistance gene in ovarian carcinomas.
Cancer Res.
1989;
49
5062-5065
-
5
Cassinelli G, Supino R, Perego P, Polizzi D, Lanzi C, Pratesi G, Zunino F.
A role for loss of p 53 function in sensitivity of ovarian carcinoma cells to taxanes.
Int J Cancer.
2001;
92
738-747
-
6
Cheng X, Kigawa J, Minagawa Y, Kanamori Y, Itamochi H, Okada M, Terakawa N.
Glutathione S-transferase-pi expression and glutathione concentration in ovarian carcinoma before and after chemotherapy.
Cancer.
1997;
79
521-527
-
7
Dabholkar M, Bostick-Bruton F, Weber C, Bohr V A, Egwuagu C, Reed E.
ERCC1 and ERCC2 expression in malignant tissues from ovarian cancer patients.
J Natl Cancer Inst.
1992;
84
1512-1517
-
8
Dijt F J, Fichtinger-Schepman A M, Berends F, Reedijk J.
Formation and repair of cisplatin-induced adducts to DNA in cultured normal and repair-deficient human fibroblasts.
Cancer Res.
1988;
48
6058-6062
-
9
Duan Z, Feller A J, Toh H C, Makastorsis T, Seiden M V.
TRAG‐3, a novel gene, isolated from a taxol-resistant ovarian carcinoma cell line.
Gene.
1999;
229
75-81
-
10
Ferrandina G, Scambia G, Damia G, Tagliabue G, Fagotti A, Benedetti Panici P, Mangioni C, Mancuso S, D'Incalci M.
Glutathione S-transferase activity in epithelial ovarian cancer: association with response to chemotherapy and disease outcome.
Ann Oncol.
1997;
8
343-350
-
11
Fichtinger-Schepman A M, van der Veer J L, den Hartog J H, Lohman P H, Reedijk J.
Adducts of the antitumor drug cis-diamminedichloroplatinum(II) with DNA: formation, identification, and quantitation.
Biochemistry.
1985;
24
707-713
-
12
Giannakakou P, Sackett D L, Kang Y K, Zhan Z, Buters J T, Fojo T, Poruchynsky M S.
Paclitaxel-resistant human ovarian cancer cells have mutant beta-tubulins that exhibit impaired paclitaxel-driven polymerization.
J Biol Chem.
1997;
272
17118-17125
-
13
Gligorov J, Lotz J P.
Preclinical pharmacology of the taxanes: implications of the differences.
Oncologist.
2004;
9
3-8
-
14
Godwin A K, Meister A, O'Dwyer P J, Huang C S, Hamilton T C, Anderson M E.
High resistance to cisplatin in human ovarian cancer cell lines is associated with marked increase of glutathione synthesis.
Proc Natl Acad Sci USA.
1992;
89
3070-3074
-
15
Goff B A, Paley P J, Greer B E, Gown A M.
Evaluation of chemoresistance markers in women with epithelial ovarian carcinoma.
Gynecol Oncol.
2001;
81
18-24
-
16
Gonzalez V M, Fuertes M A, Alonso C, Perez J M.
Is cisplatin-induced cell death always produced by apoptosis?.
Mol Pharmacol.
2001;
59
657-663
-
17
Gottesman M M.
Mechanisms of cancer drug resistance.
Annu Rev Med.
2002;
53
615-627
-
18
Györffy B, Denkert C, Lage H, Dietel M.
Prädiktive Pathologie - Strategien zur Untersuchung der Chemoresistenz mittels Genexpressionsprofilen.
Zentralbl Gynakol.
2007;
-
19
Haldar S, Basu A, Croce C M.
Bcl-2 is the guardian of microtubule integrity.
Cancer Res.
1997;
57
229-233
-
20
Kaufmann S H, Vaux D L.
Alterations in the apoptotic machinery and their potential role in anticancer drug resistance.
Oncogene.
2002;
22
7414-7430
-
21
Kavallaris M, Kuo D Y, Burkhart C A, Regl D L, Norris M D, Haber M, Horwitz S B.
Taxol-resistant epithelial ovarian tumors are associated with altered expression of specific beta-tubulin isotypes.
J Clin Invest.
1997;
100
1282-1293
-
22
Kelley S L, Basu A, Teicher B A, Hacker M P, Hamer D H, Lazo J S.
Overexpression of metallothionein confers resistance to anticancer drugs.
Science.
1988;
241
1813-1815
-
23
Lage H, Dietel M.
Involvement of the DNA mismatch repair system in antineoplastic drug resistance.
J Cancer Res Clin Oncol.
1999;
125
156-165
-
24
Lage H, Denkert C.
Resistance to chemotherapy in ovarian carcinoma.
Recent Results Cancer Res.
2007;
176
51-60
-
25
Lage H.
ABC-transporters: implications on drug resistance from microorganisms to human cancers.
Int J Antimicrob Agents.
2003;
22
188-199
-
26
Lavarino C, Pilotti S, Oggionni M, Gatti L, Perego P, Bresciani G, Pienotti M A, Scambia G, Ferrandina G, Fagotti A, Mangioni C, Lucchini V, Vecchione F, Bolis G, Scarfone G, Zunino F.
p 53 gene status and response to platinum/paclitaxel-based chemotherapy in advanced ovarian carcinoma.
J Clin Oncol.
2000;
18
3936-3945
-
27
Mamenta E L, Poma E E, Kaufmann W K, Delmastro D A, Grady H L, Chaney S G.
Enhanced replicative bypass of platinum-DNA adducts in cisplatin-resistant human ovarian carcinoma cell lines.
Cancer Res.
1994;
54
3500-3505
-
28
Mano Y, Kikuchi Y, Yamamoto K, Kita T, Hirata J, Tode T, Ishii K, Nagata I.
Bcl-2 as a predictor of chemosensitivity and prognosis in primary epithelial ovarian cancer.
Eur J Cancer.
1999;
35
1214-1219
-
29
Materna V, Liedert B, Thomale J, Lage H.
Protection of platinum-DNA adduct formation and reversal of cisplatin resistance by anti-MRP2 hammerhead ribozymes in human cancer cells.
Int J Cancer.
2005;
115
393-402
-
30
Materna V, Pleger J, Hoffmann U, Lage H.
RNA expression of MDR1/P-glycoprotein, DNA-topoisomerase I, and MRP2 in ovarian carcinoma patients: correlation with chemotherapeutic response.
Gynecol Oncol.
2004;
94
152-160
-
31
Materna V, Surowiak P, Kaplenko I, Spancynski M, Duan Z, Zabel M, Dietel M, Lage H.
Taxol-resistance-associated gene-3 (TRAG‐3/CSAG2) expression is predictive for clinical outcome in ovarian carcinoma patients.
Virchows Arch.
2007;
450
187-194
-
32
Mills G B, Lu Y, Kohn E C.
Linking molecular therapeutics to molecular diagnostics: inhibition of the FRAP/RAFT/TOR component of the PI3K pathway preferentially blocks PTEN mutant cells in vitro and in vivo.
Proc Natl Acad Sci USA.
2001;
98
10031-10033
-
33
Ohishi Y, Oda Y, Uchiumi T, Kobayashi H, Hirakawa T, Miyamoto S, Kinukawa N, Nakano H, Kuwano M, Tsuneyoshi M.
ATP-binding cassette superfamily transporter gene expression in human primary ovarian carcinoma.
Clin Cancer Res.
2002;
8
3767-3775
-
34 Ozols R F, Schwartz P E, Eifel P J. Ovarian cancer, fallopian tube carcinoma and peritoneal carcinoma. Devita VT, Hellman S, Rosenburg SA Cancer, Principles and Practice of Oncology, 6th ed. Philadelphia; Lippincott Williams & Wilkin 2001: 1597-1632
-
35
Ozols R F.
Future directions in the treatment of ovarian cancer.
Semin Oncol.
2002;
29
32-42
-
36
Parker R J, Eastman A, Bostick-Bruton F, Reed E.
Acquired cisplatin resistance in human ovarian cancer cells is associated with enhanced repair of cisplatin-DNA lesions and reduced drug accumulation.
J Clin Invest.
1991;
87
772-777
-
37
Perego P, Giarola M, Righetti S C, Supino R, Caserini C, Delia D, Pierotti M A, Miyashita T, Reed J C, Zunino F.
Association between cisplatin resistance and mutation of p 53 gene and reduced bax expression in ovarian carcinoma cell systems.
Cancer Res.
1996;
56
556-562
-
38
Puthalakath H, Huang D C, O'Reilly L A, King S M, Strasser A.
The proapoptotic activity of the Bcl-2 family member Bim is regulated by interaction with the dynein motor complex.
Mol Cell.
1999;
3
287-296
-
39
Righetti S C, Della T G, Pilotti S, Menard S, Ottone F, Colnaghi M I, Pierotti M A, Lavarino C, Cornarotti M, Oriana S, Bohm S, Bresciani G L, Spatti G, Zunino F.
A comparative study of p 53 gene mutations, protein accumulation, and response to cisplatin-based chemotherapy in advanced ovarian carcinoma.
Cancer Res.
1996;
56
689-693
-
40
Sale S, Sung R, Shen P, Yu K, Wang Y, Duran G E, Kim J H, Fojo T, Oefner P J, Sikic B I.
Conservation of the class I beta-tubulin gene in human populations and lack of mutations in lung cancers and paclitaxel-resistant ovarian cancers.
Mol Cancer Ther.
2002;
1
215-225
-
41
Samimi G, Fink D, Varki N M, Husain A, Hoskins W J, Alberts D S, Howell S B.
Analysis of MLH1 and MSH2 expression in ovarian cancer before and after platinum drug-based chemotherapy.
Clin Cancer Res.
2000;
6
1415-1421
-
42
Scambia G, Masciullo V, Benedetti Panici P, Marone M, Ferrandina G, Todaro N, Bellacosa A, Jain S K, Neri G, Piffanelli A, Mancuso S.
Prognostic significance of ras/p 21 alterations in human ovarian cancer.
Br J Cancer.
1997;
75
1547-1553
-
43
Schondorf T, Neumann R, Benz C, Becker M, Riffelmann M, Gohring U J, Sartorius J, von Konig C H, Breidenbach M, Valter M M, Hoopmann M, Di Nicolantonio F, Kurbacher C M.
Cisplatin, doxorubicin and paclitaxel induce mdr1 gene transcription in ovarian cancer cell lines.
Recent Results Cancer Res.
2003;
161
111-116
-
44
Schuyer M, van der Burg M E, Henzen-Logmans S C, Fieret J H, Klijn J G, Look M P, Foekens J A, Stoter G, Berns E M.
Reduced expression of BAX is associated with poor prognosis in patients with epithelial ovarian cancer: a multifactorial analysis of TP53, p 21, BAX and BCL‐2.
Br J Cancer.
2001;
85
1359-1367
-
45
Sehouli J, Mustea A, Konsgen D, Lichtenegger W.
Etablierte und experimentelle Prognosefaktoren des Ovarialkarzinoms.
Zentralbl Gynakol.
2004;
126
315-322
-
46 Steward B W, Kleihues P. World Cancer Report. Lyon; IARC Press 2003
-
47
Surowiak P, Materna V, Denkert C, Kaplenko I, Spaczynski M, Dietel M, Zabel M, Lage H.
Significance of cyclooxygenase 2 and MDR1/P-glycoprotein coexpression in ovarian cancers.
Cancer Lett.
2006;
235
272-280
-
48
Surowiak P, Materna V, Kaplenko I, Spaczynski M, Dietel M, Lage H, Zabel M.
Augmented expression of metallothionein and glutathione S-transferase pi as unfavourable prognostic factors in cisplatin-treated ovarian cancer patients.
Virchows Arch.
2005;
447
626-633
-
49
Surowiak P, Materna V, Kaplenko I, Spaczynski M, Dolinska-Krajewska B, Gebarowska E, Dietel M, Zabel M, Lage H.
ABCC2 (MRP2, cMOAT) can be localized in the nuclear membrane of ovarian carcinomas and correlates with resistance to cisplatin and clinical outcome.
Clin Cancer Res.
2006;
12
7149-7158
-
50
Taniguchi K, Wada M, Kohno K, Nakamura T, Kawabe T, Kawakami M, Kagotani K, Okumura K, Akiyama S, Kuwano M.
A human canalicular multispecific organic anion transporter (cMOAT) gene is overexpressed in cisplatin-resistant human cancer cell lines with decreased drug accumulation.
Cancer Res.
1996;
56
4124-4129
-
51
Vivanco I, Sawyers C L.
The phosphatidylinositol 3-Kinase AKT pathway in human cancer.
Nat Rev Cancer.
2002;
2
489-501
-
52
Wahl A F, Donaldson K L, Fairchild C, Lee F Y, Foster S A, Demers G W, Galloway D A.
Loss of normal p 53 function confers sensitization to taxol by increasing G2/M arrest and apoptosis.
Nat Med.
1996;
2
72-79
-
53
Wani M C, Taylor H L, Wall M E, Coggon P, McPhail A T.
Plant antitumor agents. VI. The isolation and structure of taxol, a novel antileukemic and antitumor agent from Taxus brevifolia.
J Am Chem Soc.
1971;
93
2325-2327
-
54
Williams J, Lucas P C, Griffith K A, Choi M, Fogoros S, Hu Y Y, Liu J R.
Expression of Bcl-xL in ovarian carcinoma is associated with chemoresistance and recurrent disease.
Gynecol Oncol.
2005;
96
287-295
-
55
Yang X, Xing H, Gao Q, Chen G, Lu Y, Wang S, Ma D.
Regulation of HtrA2/Omi by X-linked inhibitor of apoptosis protein in chemoresistance in human ovarian cancer cells.
Gynecol Oncol.
2005;
97
413-421
-
56
Zaffaroni N, Pennati M, Colella G, Perego P, Supino R, Gatti L, Pilotti S, Zunino F, Daidone M G.
Expression of the antiapoptotic gene survivin correlates with taxol resistance in human ovarian cancer.
Cell Mol Life Sci.
2002;
59
1406-1412
Prof. Dr. med. Dr. rer nat. H. Lage
Charité Campus Mitte
Institute of Pathology
Charitéplatz 1
10117 Berlin
Email: hermann.lage@charite.de
